Cornelia de lange syndrome

Cornelia de Lange syndrome affects multiple parts of the body, resulting in characteristic facial features, limb defects, growth retardation, and intellectual disability.  Genetic testing can help to confirm a diagnosis and aid in genetic counseling for a family.

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Cornelia de Lange syndrome affects multiple parts of the body, resulting in characteristic facial features, limb defects, growth retardation, and intellectual disability.  Genetic testing can help to confirm a diagnosis and aid in genetic counseling for a family.

Disease Name 
Cornelia de Lange syndrome
Brachmann-de Lange syndrome
de Lange syndrome
Disease Information 

Cornelia de Lange syndrome (CdLS) is characterized by developmental delay and characteristic physical findings.  CdLS is estimated to occur in 1 in 10,000-30,000 births worldwide; however, this number may be an underestimate due to the broad spectrum of severity and possible undiagnosed cases.1

The most common findings in individuals with CdLS include:2

  • Pre- and postnatal growth retardation
  • Hirsutism
  • Variable limb defects, primarily of the upper limbs
  • Microcephaly
  • Facial characteristics
    • High arched eyebrows that meet in the middle
    • Small, upturned nose
    • Small, widely spaced teeth
  • Intellectual disability (ranging from mild to severe)
  • Autistic or self-destructive behaviors
  • Congenital heart defects
  • Hearing loss
  • Gastrointestinal problems

There is a range of symptoms, with both severe and mild presentations.1,2 Diagnosis can be confirmed by genetic testing. Although most cases are de novo, there are two possible inheritance patterns. Therefore, genetic testing can help clarify recurrence risks within the family. There are currently five genes implicated in CdLS:1, 3-5

Gene Mode of Inheritance
NIPBL Autosomal dominant 
RAD21 Autosomal dominant 
SMC3 Autosomal dominant 
HDAC8 X-linked dominant 
SMC1A X-linked dominant 

 

Testing Benefits & Indication 

Our CdLSNext panel includes next generation sequencing (NGS) and deletion/duplication analysis of the NIPBLSMC1AHDAC8RAD21, and SMC3 genes.  Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS.

Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.6 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed utilizing a targeted chromosomal microarray.

Test Description 

Our CdLSNext panel includes next generation sequencing (NGS) and deletion/duplication analysis of the NIPBLSMC1AHDAC8RAD21, and SMC3 genes.  Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS.

Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.6 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed utilizing a targeted chromosomal microarray

Mutation Detection Rate 

Genetic testing (gene sequencing and deletion/duplication analysis) of NIPBL, SMC1A, HDAC8, RAD21, SMC3 will detect a mutation in ~70% of clinically affected people1 (clinical sensitivity). Our CdLSNext panel can detect >99.9% of described mutations in the included genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Prenatal testing is available. 

Turnaround Time 
TEST Code Test Name TAT (days)
7040 CdLSNext (NGS and del/dup of NIPBL, SMC1A, HDAC8, RAD21, SMC3) 14 - 28 

 

Genes 
NIPBL
SMC1A
HDAC8
RAD21
SMC3
References 
  1. Ramos FJ, et al.  Clinical utility gene card for: Cornelia de Lange syndrome.  Eur J Hum Genet. 2015 Oct;23(10).
  2. Kline AD, et al.  Natural history of aging in Cornelia de Lange syndrome.  Am J Med Genet C Semin Med Genet. 2007 Aug 15;145C(3):248-60.
  3. Deardorff MA, et al.  Cornelia de Lange Syndrome.  September 16, 2005 [Last update: October 27, 2011]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  4. Deardorff MA, et al.  RAD21 mutations cause a human cohesinopathy.  Am J Hum Genet. 2012 Jun 8;90(6):1014-27.
  5. Deardorff MA, et al.  HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.  Nature. 2012 Sep 13;489(7415):313-7. 
  6. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.